DESCRIPTION: (Adapted from the application). Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by prominent impairments in memory, which have been attributed to synaptic loss and altered synaptic plasticity in neural circuits subserving memory. Elucidation of the cellular and molecular mechanisms underlying memory formation may therefore lead to novel therapeutic strategies. Manipulation of the mouse genome has been exploited to address the contribution of specific genes to neural phenomena associated with synaptic plasticity, including hippocampal long-term potentiation (LTP), spatial learning and memory. The applicant and colleagues have recently developed methodology that enables gene disruption or transgene expression in restricted regions of the postnatal murine brain. These techniques have permitted disruption of NMDA receptor function exclusively in pyramidal cells of hippocampal area CA1, demonstrating a requirement for NMDA receptor-dependent plasticity at CA1 synapses in hippocampal LTP, place cell formation, and spatial learning and memory. The proposal is to employ this approach to test the hypothesis that mitogen-activated protein kinase (MAPK) function is required for synaptic plasticity and associated phenomena in the mammalian brain. The Ras/MAPK cascade is a highly-conserved signalling pathway that mediates cellular responses to a variety of stimuli. The extracellular-signal regulated kinase (ERK) subfamily pathway is activated by Ras-dependent and -independent mechanisms in response to stimuli associated with synaptic plasticity in neurons, including neurotrophins, glutamate and calcium. However, the role of the ERK pathway in learning and memory in the mammalian brain remains to be established. Mice transgenic for a dominant-negative form of MAPK/ERK kinase (MKK1) will be generated in order to inhibit ERK function in subregions of the postnatal brain. The resulting mice will be analyzed for hippocampus-dependent and hippocampus-independent spatial learning and memory, hippocampal and neocortical LTP and LTD, hippocampal place-cell formation, and cAMP response element-binding protein (CREB)-dependent gene expression.